1. Field of the Invention
The present invention relates to new aromatic esters and thioesters, to a process for their preparation and to their use in human and veterinary medicine and in cosmetic compositions. These new aromatic esters and thioesters are usefully employed in the topical and systemic treatment of dermatologic ailments linked to a keratinization disorder (differentiation-proliferation) and dermatologic disorders, or others, having inflammatory and/or immunoallergic components and in conjunctive tissue degeneration illnesses. They also exhibit an antitumoral activity. Moreover, these derivatives can be used in the treatment of atopy. be it cutaneous or respiratory, and in the treatment of rheumatoid psoriasis.
The compounds of the present invention also find use in the ophthalmologic field and principally in the treatment of corneopathies.
The esters and thioesters, in accordance with the present invention, can be represented by the following formula: ##STR2## wherein X represents oxygen or sulfur,
R represents --CH.sub.2 OH, --CH(OH)--CH.sub.3, --COOR.sub.5 or ##STR3## R.sub.5 represents hydrogen, lower alkyl, lower alkenyl, monohydroxyalkyl or polyhydroxyalkyl, PA0 r' and r" represent hydrogen, lower alkyl, monohydroxyalkyl, polyhydroxyalkyl, aryl or benzyl optionally substituted, the residue of an amino acid or aminated sugar, or r' and r" together with the nitrogen atom to which they are attached form a heterocycle, PA0 R.sub.2 represents .alpha.,.alpha.'-disubstituted alkyl having 4-12 carbon atoms or mono- or polycyclic cycloalkyl having 5-12 carbon atoms whose carbon linkage is trisubstituted, PA0 R.sub.3 represents hydrogen, lower alkyl, -Si(CH.sub.3).sub.2 R'.sub.3 wherein R'.sub.3 represents lower alkyl, and PA0 R.sub.4 represents hydrogen or lower alkyl, and PA0 the salts of said aromatic esters and thioesters of formula (I) when R.sub.5 represents hydrogen. PA0 4-[3-(1-adamantyl)-4-methoxybenzoylthio]benzoic acid, PA0 4-[3-(1-methylcyclohexyl)-4-methoxybenzoyloxy]benzoic acid, PA0 4-[3-(1-methylcyclohexyl)-4-benzoylthio]benzoic acid, PA0 4-[3-(1,1-dimethyldecyl)-4-methoxybenzoyloxy]benzoic acid, PA0 4-[3-(1,1-dimethyldecyl)-4-methoxybenzoylthio]benzoic acid, PA0 4-[3-(1-adamantyl)-4-hydroxybenzoyloxy]benzoic acid, PA0 4-[3-(1-adamantyl)-4-hydroxybenzoylthio]benzoic acid, PA0 ethyl 4-[3-(1-adamantyl)-4-ethyl 4-methoxybenzoyloxy]benzoate, PA0 ethyl 4-[3 -(1-adamantyl)-4-methoxybenzoylthio]benzoate, PA0 N-ethyl 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]benzamide, PA0 the morpholide of 4-[3-(I-adamantyl)-4-methoxybenzoylthio]benzoic acid, PA0 allyl 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]benzoate, PA0 4-[3-tert.butyl-4-methoxybenzoylthio]benzoic acid, PA0 methyl 4-[3-(1-adamantyl)-4-methoxybenzoylthio]benzoate, PA0 N-ethyl 4-[3-(1-adamantyl)-4-methoxybenzoylthio]benzamide, PA0 2-hydroxyethyl 4-[3-(1-adamantyl)-4-methoxybenzoylthio]benzoate, PA0 4-[3-(1-adamantyl)-4-t.ert.butyldimethyl-silyloxybenzoylthio]benzoic acid, PA0 allyl 4-[3-(1-adamantyl)-4-hydroxybenzoyloxy]benzoate, PA0 3-methyl 4-[3-(I-adamantyl)-4-methoxybenzoyloxy]benzoic acid, PA0 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]benzoic aldehyde, PA0 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]benzyl alcohol. PA0 4-[3-(1-adamatyl)-4-methoxybenzoylthio]benzamide, PA0 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]benzamide, PA0 N,N-dimethyl,4-[3-(1-adamantyl)4-methoxybenzoyloxy]benzamide and, PA0 3-tert.butyl-4-[3-(1-adamantyl)-4-methoxybenzoyloxy]benzoic acid.
When the compounds in accordance with the present invention are provided in the form of salts, those preferred are the salts of an akali metal or an alkaline earth metal or a zinc salt or an organic amine salt.
By lower alkyl is meant a radical having 1-6 carbon atoms and principally methyl, ethyl, isopropyl, butyl and tert.butyl.
By .alpha.,.alpha.'disubstituted alkyl having 4-12 carbon atoms is meant principally a tert.butyl, 1,1-dimethylpropyl, 1-methyl-1-ethylpropyl, 1 methyl-1-ethylhexyl or 1,1-dimethyldecyl radical.
By monohydroxyalkyl is meant a radical having 2 or 3 carbon atoms and principally a 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radical.
By polyhydroxyalkyl is meant a radical containing 3-6 carbon atoms and 2-5 hydroxyl groups, such as 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl or the residue of pentaerythritol.
By aryl is meant phenyl or phenyl substituted by halogen, hydroxy or nitro.
By mono- or polycyclic cycloalkyl having 5-12 carbon atoms whose carbon linkage is trisubstituted is meant 1-methylcyclohexyl or 1-adamantyl.
By amino acid residue is meant a residue derived, for example, from lysine or glycine.
By residue of an aminated sugar is meant a residue derived, for example, from glucosamine, galactosamine or mannosamine.
When the r' and R" radicals taken together form a heterocycle, the heterocycle preferably is a piperidino, piperazino, morpholino, pyrrolidino or 4-(2-hydroxyl ethyl) piperazino heterocycle.
Representative compounds of formula (I) above include principally the following:
4-[3-(1-adamantyl)-4-methoxybenzoyloxy]benzoic acid,
The present invention also relates to a process for preparing the compounds of formula (I) in accordance with the following reaction scheme: ##STR4##
The principal step of this preparation comprises reacting, in an anhydrous medium, in an organic solvent such as tetrahydrofuran or methylene chloride containing a tertiary amine (pyridine or triethylamine), an activated form of a substituted benzoic acid, for example, an acid chloride (1), or a mixed anhydride, with a p-hydroxy or p-thio benzoic acid, optionally substituted in position 3 (2), the reaction being carried out at ambient temperature with stirring.
The (Ia) acids thus obtained can be converted in a known manner into a corresponding acid chloride which, when treated with an alcohol (R.sub.5 OH) or an ##STR5## gives the corresponding ester (Ib) or amide (Ic).
The compounds of formula (Ia) in which X represents oxygen can also be prepared in accordance with the following reaction scheme: ##STR6##
The reaction of the acid chloride (1) with an allyl p-hydroxybenzoate (3), optionally substituted at the 3 position, in the presence of a tertiary amine such as pyridine or triethylamine, leads to allylic esters (Id). Synthesis of the free acid can be effected by means of a catalyst such as certain transition metal complexes, for example, tris(triphenylphosphine) rhodium (1) chloride or tetrakis(triphenylphosphine) palladium (o) in the presence of a secondary amine.
The present invention also relates to a medicine comprising the compounds of formula (I) such as defined above.
The compounds in accordance with the present invention exhibit good stability to light and oxygen.
The compounds of the present invention exhibit excellent activity in the inhibition test of ornithine decarboxylase in nude rats, after induction, by "tape stripping", M. Bouclier et al., Dermatologica, 169, No.4, 1984. This test is recognized as a measure of the inhibiting activity of certain compounds on cellular proliferation phenomena.
The compounds of the present invention are particularly active in the differentiation test of embryonic tetracarcinoma cells of mice (F9 cells) (Cancer Research 43, p.5268, 1983).
Finally, the new compounds are characterized by the introduction in the chemical structure of an ester or thioester linkage which is highly sensitive to the action of various esterases in vivo, which leads to the rapid inactivation of molecules by conversion into biologically inactive fragments.
The compounds of the present invention are indeed particularly suitable in the following treatment fields:
(1) for the treatment of dermatologic ailments linked to keratinization disorder causing differentiation and proliferation and principally for the treatment of acne vuloaris. comedons, polymorphs, nodulokystic acne, conglobata, senile acne, secondary acne such as solar acne, medicinal acne or professional acne;
(2) for the treatment of other types of keratinization disorders and principally ichtysoses, ichthyosiform conditions, Darier malady, palmoplantary keratodermies, leucoplasies and leucoplasiform conditions and lichen;
(3) for the treatment of dermatologic ailments linked to a keratinization disorder having an inflammatory and/or immunoallergic component and principally, all forms of psoriasis, be they cutaneous, mucous or ungual, and even psoriasic rheumatism, or again cutaneous atopies, such as eczema, or respiratory atopies; the compounds can also be used in certain inflammatory ailments not exhibiting any keratinization disorder;
(4) for the treatment of all dermic or epidermic proliferations that are benign or malignant, that are either of viral origin such as common warts, plane warts and epidermodysplasie verruciform, the proliferation being able to be induced by ultraviolet radiations, principally in the case of baso epithelioma and cellular spino;
(5) for the treatment of other dermatologic disorders such as blistery dermatoses and collagen maladies;
(6) for the treatment of ophthalmologic disorders, and principally for the treatment of corneopathies;
(7) for combatting against ageing of the skin, be it photoinduced or not; and
(8) to prevent or heal scars of epidermic or dermic atoPies. induced by local or systemic corticosteroids, or any other form of cutaneous atophy.
The present invention also relates to medicinal compositions containing at least one compound of formula (I), such as defined above, or one of its salts.
The present invention thus relates to a new mecidical composition, intended principally for the treatment of the ailments mentioned above, comprising in a pharmaceutically acceptable support at least one compound of formula (I) and/or one of its salts.
The compounds according to the present invention are generally administered to a human or animal host at a daily dosage of about 0.01 mg/kg to 100 mg/kg of body weight.
As the vehicle or support for these compositions any conventional vehicle can be employed, the active component being found either in the dissolved state, or in the dispersed state, in said vehicle.
The administration of the compounds of the present invention can be effected enterally, parenterally, topically or ocularly.
When administered enterally, the medicines can be provided in the form of tablets, gelules, lozenges, syrups, suspensions, solutions, powders, granules or emulsions.
When administered parenterally, the medicinal compositions can be provided in the form of solutions or suspensions for perfusion or injection.
When administered topically, the pharmaceutical compositions, based on the compounds according to the present invention, can be provided in the form of ointments, tinctures, creams, salves, powders, pads, impregnated tampons, solutions, lotions, gels, sprays or suspensions.
These topically applied compositions can be provided in anhydrous form or in aqueous form, according to clinical indications.
When administered ocularly, the medicinal composition is principally in the form of an eyewash.
The compounds of formula I, according to the present invention, are also useful in the cosmetic field, and in particular in body and hair hygiene compositions and principally for the treatment of skin having acne tendencies, to improve the growth of hair, i.e., to promote the growth of existing hair follicles, to combat hair loss, to combat against an oily appearance of the skin or hair, in the prevention or treatment of the harmful effects of the sun or in the treatment of physiologically dry skin.
The present invention thus relates to a cosmetic composition containing, in a cosmetically acceptable vehicle, an effective amount of at least one compound of formula I or one of its salts, this composition being provided principally in the form of a lotion, gel, soap or shampoo.
The concentration of the compound of formula I in these cosmetic compositions is between 0.0001 and 0.1 percent by weight and preferably between 0.001 and 0.01 percent by weight, based on the total weight of the composition.
The medicinal and cosmetic compositions according to the present invention can contain inert or even pharmacodynamic or cosmetically active additives and, principally: hydrating agents such as thiamorpholinone and its derivatives or urea; antiseborrheic or anti-acne agents such as S-carboxymethylcysteine, S-benzylcysteamine, their salts and their derivatives, tioxolone or benzoylperoxide; antibiotics such as erythromycin and its esters, neomycin, tetracyclines or 4,5-polymethylene-3-isothiazolinones; agents promoting the growth of hair, such as "Minoxidil" (2,4-diamino-6-piperidino-3-pyrimidine oxide) and its derivatives, Diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine-1,1-dioxide) and Phenytoin (5,5-diphenyl-2,4-imidazolidine dione); steroidal and non-steroidal anti-inflammatory agents; carotenoids and, principally, .beta.-carotene; anti-psoriasic agents such as anthralin and its derivatives and 5,8,11,14-eicosatetraynoic and 5,8,11-eicosatriynoic acids, and their esters and amides.
The compositions according to the present invention can also include flavor improving agents, preservatives, stabilizers, humidity regulating agents, pH regulating agents, osmotic pressure modifying agents, emulsifiers, UV-A and UV-B filters, and antioxidants such as .alpha.-tocopherol, butylhydroxyanisole or butylhydroxytoluene.